RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex

Abstract

Background Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, frequently accompanied by metastasis and aerobic glycolysis. Cancer cells adjust their metabolism by modulating the PKM alternative splicing and facilitating PKM2 isoform expression. Therefore, identifying factors and mechanisms that control PKM alternative splicing is significant for overcoming the current challenges in ATC treatment. Results In this study, the expression of RBX1 was largely enhanced in the ATC tissues. Our clinical tests suggested that high RBX1 expression was significantly related to poor survival. The functional analysis indicated that RBX1 facilitated the metastasis of ATC cells by enhancing the Warburg effect, and PKM2 played a key role in RBX1-mediated aerobic glycolysis. Furthermore, we confirmed that RBX1 regulates PKM alternative splicing and promotes the PKM2-mediated Warburg effect in ATC cells. Moreover, ATC cell migration and aerobic glycolysis induced by RBX1-mediated PKM alternative splicing are dependent on the destruction of the SMAR1/HDAC6 complex. RBX1, as an E3 ubiquitin ligase, degrades SMAR1 in ATC through the ubiquitin–proteasome pathway. Conclusion Overall, our study identified the mechanism underlying the regulation of PKM alternative splicing in ATC cells for the first time and provides evidence about the effect of RBX1 on cellular adaptation to metabolic stress.

ZNF471 Interacts with BANP to Reduce Tumour Malignancy by Inactivating PI3K/AKT/mTOR Signalling but is Frequently Silenced by Aberrant Promoter Methylation in Renal Cell Carcinoma

“…BANP (also known as SMAR1) is encoded by a gene located on chromosome 16q24.3 in humans and is expressed in heart, liver, spleen, lung, kidney, brain and thymus tissues, with the highest expression in the thymus 36 . The main role of BANP in tumours is to regulate the cell cycle, prevent tumour metastasis and invasion through the transforming growth factor (TGF-β) pathway, and regulate cytoskeletal dynamics and the NF-κB signalling pathway 37 . Studies have found that BANP could arrest the cell cycle at the G1/S and G2/M boundaries, and the mechanism might be p53 activation by BANP, but it has not been fully elucidated 38 .…”

Ubiquitin-modifying enzymes in thyroid cancer：Mechanisms and functions

“…2.Promote MTC apoptosis and enhance cancer cell sensitivity to ionizing radiation [ 59 , 62 , 65 , 68 , 69 , 139 , 140 ] MDM4 PTC, ATC p53 1.Downregulate with tumor progression in PTC and associate with PTC non-multifocality 2. Increase survival of mice with wild-type p53 when reduced in ATC [ [63] , [64] , [65] ] Praja2 PTC, ATC PKA cAMP/Praja2/PKA 1.Overexpressed in PTC, Activate cAMP signaling pathway, promote proliferation 2.Low expression in ATC, can be used to monitor the degree of tumor malignancy [ 124 ] Rbx1 PTC, ATC SMAR1, NRF2 Rbx1/SMAR1/PKM1 promote invasion, migration, promote carcinogenic potential, inhibit autophagy [ 130 , 152 ] RNF150 PTC ASK1 RNF150/ASK1/p38 Downregulated in PTC, inhibit MAPK signaling pathway, inhibit proliferation, migration [ 129 ] SH3RF3 PTC miR-192-5p/SH3RF3 Promote invasion, migration [ 118 ] SKP2 PTC, FTC, ATC p27, PHLPP1 1.SKP2/PHLPP1/AKT 2. SKP2/p27 Promote proliferation, inhibit apoptosis and autophagy [ 55 , 97 , 114 ] …”

“…As an E3 ligase, RBX1 ubiquitinates scaffold/matrix attachment region binding protein 1 (SMAR1), down-regulating its expression. The SMAR1/histone deacetylase 6 (HDAC6) complex, involved in pyruvate kinase M1/2 (PKM) alternative splicing, is down-regulated as a result, down-regulating PKM1 and up-regulating PKM2, ultimately promoting ATC development by enhancing the Warburg effect [ 152 ].…”